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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
- Source :
- Jakobsdottir , J , van der Lee , S , Bis , JC , Chouraki , V , Li-Kroeger , D , Yamamoto , S , Grove , ML , Naj , A , Vronskaya , M , Salazar , JL , DeStefano , AL , Brody , JA , Smith , AV , Amin , N , Sims , R , Verbaas , C , Choi , SH , Satizabal , CL , Lopez , OL , Beiser , A , Ikram , A , Garcia , ME , Hayward , C , Varga , TV , Ripatti , S , Franks , PW , Hallmans , G , Rolandsson , O , Jansson , JH , Porteous , DJ , Salomaa , V , Eiriksdottir , G , Rice , KM , Bellen , HJ , Levy , D , Uitterlinden , A , Emilsson , V , Rotter , JI , Aspelund , T , O'Donnell , CJ , Fitzpatrick , AL , Launer , LJ , Hofman , B , Wang , LS , Williams , J , Schellenberg , GD , Boerwinkle , E , Psaty , BM , Seshadri , S , Shulman , JM , Gudnason , V & Duijn , C 2016 , ' Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease ' , PLoS Genetics (online) , vol. 12 , no. 10 .
- Publication Year :
- 2016
-
Abstract
- We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.
Details
- Database :
- OAIster
- Journal :
- Jakobsdottir , J , van der Lee , S , Bis , JC , Chouraki , V , Li-Kroeger , D , Yamamoto , S , Grove , ML , Naj , A , Vronskaya , M , Salazar , JL , DeStefano , AL , Brody , JA , Smith , AV , Amin , N , Sims , R , Verbaas , C , Choi , SH , Satizabal , CL , Lopez , OL , Beiser , A , Ikram , A , Garcia , ME , Hayward , C , Varga , TV , Ripatti , S , Franks , PW , Hallmans , G , Rolandsson , O , Jansson , JH , Porteous , DJ , Salomaa , V , Eiriksdottir , G , Rice , KM , Bellen , HJ , Levy , D , Uitterlinden , A , Emilsson , V , Rotter , JI , Aspelund , T , O'Donnell , CJ , Fitzpatrick , AL , Launer , LJ , Hofman , B , Wang , LS , Williams , J , Schellenberg , GD , Boerwinkle , E , Psaty , BM , Seshadri , S , Shulman , JM , Gudnason , V & Duijn , C 2016 , ' Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease ' , PLoS Genetics (online) , vol. 12 , no. 10 .
- Notes :
- application/pdf, und
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1313620532
- Document Type :
- Electronic Resource